Investigating the Process of Cell Invasion

A/Prof Geraldine O'Neill

Research Idea

Understanding the machinery that drives cancer cells to spread away from the primary tumour and invade secondary sites in the body (known as invasion and metastasis) will guide the development of therapies that can specifically target invasive cancer.

Problem

Progression to invasive cancer is the leading cause of death for patients with cancer, irrespective of cancer type. Because the mechanisms of cell invasion are poorly understood, there are few therapies directed against invasive cancer. We urgently need to understand the events that control invasion at the cellular and molecular levels if we are to slow or prevent this process.

1) 2D GBM cells - Eshana De Silva

2) GBM cells implanted in gel - Dr Ellen De Leon

3) GBM brain slice - Dr Ellen De Leon

Solution

The conventional approach to investigating cancer invasion is to use a two-dimensional (2D) cell-culture assay, in which cancer cells migrate across a flat, hard surface. However, these assays do not recapitulate the 3D environment that is encountered by invasive cancer cells in the body. Our unique approach is to use bio-engineered 3D cell-culture models. These models more closely mimic the natural organisation in the body and allow us to investigate how cancer cells interpret the biophysical cues, such as tissue stiffness and 3D architecture, of the surrounding tissue. Our 3D models replicate key features of the brain environment, allowing us to study which factors are important for brain cancer cell invasion. These models are better than the conventional approach at predicting how cancer cells behave in the brain.

Approach

We have only just begun to realise that invading cancer cells respond to biophysical cues within the tissues through which they are invading. Thus, targeting this mechanism is a completely new avenue in the treatment of invasive cancer. We aim to uncover the molecules that the cancer cells use to sense and respond to external biophysical cues so that we can block cancer cell invasion. Our goal is to find the molecules that mediate brain cancer cell response to biophysical cues in the brain so that we can use molecularly targeted medicines to block the invasive cell populations.

Challenge

To accurately predict how cancer cells migrate within the brain, 3D model systems must mirror the physical characteristics of the brain not just at the primary tumour site but also at the sites where invasive tumours form. In addition, migrating cancer cells interact with many tissue structures (such as blood vessels) and many cell types (such as immune cells), so these must be incorporated into the models. These features are different for each type of tumour, so we cannot build our models by relying on findings based on other cancers and must determine the appropriate set-up for each type of brain cancer. Designing such faithful models is a challenge.

Impact

Understanding invasion by glioblastoma, the most common malignant primary brain cancer in adults, is the first step towards new specific treatments with fewer side effects. There are few treatment options for glioblastoma and most don’t discriminate between tumour and healthy brain. We therefore urgently need treatment approaches to specifically target the invasive cells. Our research exploits the response of glioblastoma cells to the brain environment. As very few healthy brain cells are invasive, targeting the invasive glioblastoma cell fraction should reduce toxicity to the healthy brain, thereby improving the quality of life for patients. Moreover, invading glioblastoma cells can also damage the brain tissue, so slowing invasion would also improve quality of life. Given the current low survival rate, new, targeted, therapies have the potential to significantly improve survival.

Team & Partners

Dr Ellen De Leon is a key postdoctoral researcher in our research group. She carries out the 3D invasion assays and oversees their quality control and validation. We also collaborate with colleagues with expertise in biophysics and tissue engineering to advance the development of our 3D models. Our group is part of the Brain Cancer Discovery Collaborative (BCDC), a national team of brain cancer researchers. In addition to research into the cell’s invasion machinery, we are using our 3D models to assess the effectiveness of potential treatments (generated by BCDC researchers) at preventing invasion. This is a cheap and rapid approach to screening a range of compounds.

THIS PROJECT IS PART OF THE BCDC

The BCDC brings together eminent members of the scientific and medical research community across Australia and is committed to finding treatments and a cure for brain cancer.